Structure and dynamics of the ASB9 CUL-RING E3 Ligase.

Nature Communications
Ryan J LumpkinElizabeth A Komives

Abstract

The Cullin 5 (CUL5) Ring E3 ligase uses adaptors Elongins B and C (ELOB/C) to bind different SOCS-box-containing substrate receptors, determining the substrate specificity of the ligase. The 18-member ankyrin and SOCS box (ASB) family is the largest substrate receptor family. Here we report cryo-EM data for the substrate, creatine kinase (CKB) bound to ASB9-ELOB/C, and for full-length CUL5 bound to the RING protein, RBX2, which binds various E2s. To date, no full structures are available either for a substrate-bound ASB nor for CUL5. Hydrogen-deuterium exchange (HDX-MS) mapped onto a full structural model of the ligase revealed long-range allostery extending from the substrate through CUL5. We propose a revised allosteric mechanism for how CUL-E3 ligases function. ASB9 and CUL5 behave as rigid rods, connected through a hinge provided by ELOB/C transmitting long-range allosteric crosstalk from the substrate through CUL5 to the RBX2 flexible linker.

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Citations

Jan 13, 2021·Proceedings of the National Academy of Sciences of the United States of America·Panpan HouDeyin Guo
Dec 4, 2020·Molecular & Cellular Proteomics : MCP·Ryan J LumpkinElizabeth A Komives
Dec 4, 2020·Current Opinion in Structural Biology·Sarath Ramachandran, Alessio Ciulli
Apr 2, 2021·Journal of Chemical Information and Modeling·Antonella PaladinoMichele Ceccarelli
Sep 26, 2021·Cell·Andrew G ManfordMichael Rape
Jan 27, 2022·Journal of Molecular Neuroscience : MN·Sha LiuDeqin Geng

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Methods Mentioned

BETA
neddylation
amide exchange
amide
size-exclusion chromatography
electrophoresis

Software Mentioned

Phenix
USCF Chimera
DogPicker py
MotionCor2
EMBOSS
Rosetta Relax
MODELLER
Rosetta FastRelax
Relion
Rosetta

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